Principal Investigator/Program Director (Last, first, middle): Imrie, Allison 1 R21 AI074831-01A2 Dengue causes significant morbidity and mortality in tropical and subtropical regions, where it is endemic. Infection with any of the 4 dengue viruses may be asymptomatic or may lead to a self-limiting febrile illness known as dengue fever. A small proportion of dengue fever cases progress to dengue hemorrhagic fever (DHF), or to the most severe form of the disease, dengue shock syndrome (DSS). The pathogenesis of DHF/DSS is not well understood, but epidemiological observations suggest that disease severity is associated with secondary infection with heterologous dengue serotypes. The objective of this research project is to study the role of CD4+ and CD8+ T lymphocytes in the human response to primary and sequential dengue infection, testing the overarching hypothesis that dengue virus (DV)-specific memory T cells may be preferentially activated by altered peptide ligands (APL) representing heterologous serotypes to produce proinflammatory cytokines or other soluble factors which may contribute to the immunopathogenesis of DHF/DSS. Our preliminary finding that memory CD8+ T cells from individuals with well defined dengue infections may be preferentially activated by APL representing previously encountered dengue virus to secrete enhanced levels of proinflammatory cytokines, coupled with altered cytolytic function, will be extended in a systematic analysis of cellular immunity in subjects with a known sequence of dengue virus infections. We will extend and confirm our findings that the polyclonal, heterogeneous DV-specific memory T cell population is capable of responding to a range of antigens, however at the clonal level the altered, skewed phenotype induced by stimulation with variant superagonist peptides, and the enhanced structural avidity for previously encountered antigens, may not necessarily be protective but may contribute to pathogenesis of dengue virus infection.